Vaccination strategies represent an exciting new approach to the treatment of CEA-expressing malignancies. The present trial will employ two novel anti-CEA vaccines; Vaccinia-CEA(6D)-TRICOM and Fowlpox-CEA(6D)-TRICOM. These recombinant (r) poxvirus vectors infect professional antigen presenting cells which in turn present peptides derived from the full length CEA molecule. These viral vectors also direct the expression of three co-stimulatory molecules (B7-1, ICAM-1, and LFA-3) each of which is capable of providing a critical second activating signal to antigen-specific T cells. Priming with the vaccinia vector and boosting with the fowlpox vector enhances the formation of a CEA-specific T cell response. GM-CSF is also given at the vaccination site as it promotes the activation, maturation, and migration of antigen presenting cells. We plan to evaluate the safety and efficacy of the vaccine regimen when combined with interferon-alpha-2b (IFN-a2b). IFN-a will be combined with this vaccine regimen because of its ability to rapidly upregulate CEA expression in patient tumor cells. Also, IFN-a upregulates tumor cell expression of MHC class I molecules that are critical for the presentation of tumor antigens to cytolytic T cells. We therefore hypothesize that IFN-a treatments will increase CEA and MHC Class I expression on patient tumor cells leading to an improved anti-CEA immune response following vaccination. All patients will receive a priming vaccination with rVaccinia-CEA(6D)-TRICOM followed at monthly intervals by boosting vaccinations with rFowlpox-CEA(6D)-TRICOM. All vaccinations will be given with GM-CSF (sargramostim) 100 mcg subcutaneously (s.c.) at the vaccine site starting on the day of vaccination and continuing for a total of 4 days. Patients will receive three s.c. doses of IFN-a2b following each vaccination. The IFN-a2b component of therapy will be dose-escalated over four dose levels (1, 3, 6, or 9 million units) in cohorts of three patients. Tumors will be biopsied and examined to determine the effect of IFN-a2b administration on tumor expression of CEA and MHC class I. The formation of an anti-CEA T cell response will be evaluated by a panel of immunologic correlative studies. These analyses will allow us to determine whether the expression of the CEA tumor antigen can be modulated by cytokine treatment and if this translates into an improved anti-tumor response.